DESCRIPTION: (Applicant's Abstract) The development of invasive and metastatic cancer requires that tumor cells have the capacity to withstand apoptotic stimuli as they invade and migrate through extracellular matrix. The applicant has identified a tyrosine kinase in human tumors called focal adhesion kinase (FAK), which appears to be a critical signaling molecule for these host-tumor interactions. P125FAK becomes overexpressed as tumors become invasive and metastatic and attenuation of the FAK signaling pathway causes tumor cells to lose their adhesion properties and become apoptotic. The hypothesis is that FAK is overexpressed to act as a "survival signal" to protect the tumor from undergoing apoptosis, and that FAK and its signaling components are excellent targets for cancer therapeutics. This application focuses on the biology of FAK in the development of cancer and on the biological mechanism by which attenuation of FAK signaling causes tumor cell apoptosis. To test this hypothesis, the new monoclonal antibody developed by the applicant will be used to analyze p125FAK expression in paraffin-embedded tissue sections from three large population-based, case control studies of breast cancer, colon cancer, and melanoma. The mechanism(s) of apoptotic signaling triggered by elimination of FAK signaling in BT-474 breast cancer cells will be examined using a dominant negative carboxy-terminal FAK construct, (FAK-CD). Preliminary studies have suggested that the apoptotic mechanisms involve caspase 8/FADD pathways. Using mutagenesis and phage display strategies, the critical binding domain(s) in FAK-CD that triggers the apoptotic cascade will be defined, as well as the domain of its binding partner(s). Finally, the survival signals that make specific tumor cell lines more resistant to the effects of FAK downregulation will be defined. The identification of these molecular mechanisms will allow the ultimate development of FAK-based therapeutics of human malignancies.